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Purity: ≥98%
| Targets |
Fuzuopali targets poly(ADP-ribose) polymerase (PARP), specifically PARP1, with an IC50 of 1.46 ± 0.72 nM. PARP enzymes are involved in DNA repair, and their inhibition is particularly effective in cancer cells with deficiencies in homologous recombination repair (HR), such as those with BRCA1/2 mutations. By inhibiting PARP, fuzuopali induces synthetic lethality in HR-deficient tumor cells, leading to DNA damage accumulation and cell death.
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| ln Vitro |
BRCA2-deficient V-C8 cells and BRCA1-deficient MDA-MB-436 cells showed concentration-dependent increases in γH2AX levels in response to fluzoparib (30 μM; 24 h); however, BRCA-proficient V cells did not exhibit this effect. ‐C8#13‑5 cells [1]. In MDA-MB-436 cells, fluzoparib (10μM) activates the G2/M checkpoint by raising pCDK1 and cyclin B levels over the course of 24 hours [1]. HR-deficient MDA-MB-436 cells undergo G2/M arrest and apoptosis when exposed to fluzoparib (10 μM; 72 h), which concentration-dependently enhances caspase-3, -8, and -9 processing [1]. When it comes to HR-deficient cells, such as BRCA1-deficient cells (UWB1.289), MDA-MB-436, BRCA2-deficient cells (V-C8), BRCA1-deficient cells, BRCA2 mutant cells (MX-1), and BRCA1 hypermethylated cells, pazoparib is preferentially effective against them. The IC50 values of (OVCAR-8) cells are 0.51μM, 1.57μM, 0.053μM, 1.57μM, and 1.43μM, appropriately. Both V-C8#13-5 and UWB1.289 BRCA1 have IC50 values of greater than 10μM[1]. These cells are HR competent.
In vitro, fuzuopali shows preferential activity against HR-deficient cells. In BRCA2-deficient V-C8 cells and BRCA1-deficient MDA-MB-436 cells, it induces a concentration-dependent increase in γH2AX levels (a marker of DNA damage) at 30 μM for 24 hours. In MDA-MB-436 cells, 10 μM fuzuopali activates the G2/M checkpoint and induces apoptosis after 72 hours, leading to concentration-dependent processing of caspase-3, -8, and -9. IC50 values in various HR-deficient cell lines range from 0.053 μM to 1.57 μM. |
| ln Vivo |
The pharmacokinetic characteristics of fluzoparib (oral gavage; 0.3, 1, or 3 mg/kg; single dose) in female Balb/cA nude (5–6 week old) mice harboring MDA-MB-436 are good. Fluzoparib is quickly absorbed and eliminated from the blood after a single oral dosage; within two hours, plasma concentrations of the medication quickly reach their maximal levels. On the other hand, fluzopanib concentrations in tumors (57.9 μg/g, 39.3 μg/g, and 85.6 μg/g at dosages of 0.3, 1, and 3 mg/kg) persisted even 24 hours after delivery. g), correspondingly] [1]. In nude mice, fluzoparib (oral gavage; 30 mg/kg; 21 days) does not significantly cause weight loss, but it does significantly suppress tumor growth, with an inhibition rate of 59% (day 21) at 30 mg/kg. MDA-MB-436? (deficiency in BRCA1)? model [1]. When apatinib, paclitaxel, or cisplatin were administered orally by gavage (BID; 21 days) along with fluzoparib (3 mg/kg), the corresponding growth inhibition rates were 61.4%, 55.3%, and 72.8%. On day 21, the combinations of apatinib, cisplatin, and fluzoparib or apatinib, paclitaxel, and apatinib resulted in growth suppression in vivo by 84.9% and 75.6%, respectively. Weight loss was seen with the 2-drug combination of fluzoparib and cisplatin as well as the 3-drug combination of apatinib, cisplatin, and fluzoparib; no appreciable toxicity was seen with the other combinations [1].
In vivo, fuzuopali demonstrates good pharmacokinetic properties in mouse models. In female Balb/cA nude mice bearing MDA-MB-436 tumors, oral administration results in rapid absorption, with peak plasma concentrations reached within 2 hours. Notably, fuzuopali concentrations in tumors persist for up to 24 hours after a single oral dose, with levels of 57.9, 39.3, and 85.6 μg/g at doses of 0.3, 1, and 3 mg/kg, respectively. The compound has demonstrated antitumor activity in xenograft models. |
| Enzyme Assay |
In vitro enzyme assays for fuzuopali typically involve measuring its inhibition of PARP1 enzymatic activity. The compound's IC50 of 1.46 ± 0.72 nM is determined using purified PARP1 enzyme and its substrate, NAD+, in a biochemical assay.
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| Cell Assay |
In vitro cell-based assays for fuzuopali assess its effect on DNA damage and cell viability in HR-deficient and HR-proficient cancer cell lines. Key endpoints include the measurement of γH2AX levels as a marker of DNA damage, cell cycle analysis, and apoptosis assays. For example, treatment of MDA-MB-436 cells with 10 μM fuzuopali for 72 hours is used to study G2/M arrest and caspase activation.
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| Animal Protocol |
In vivo animal experiments for fuzuopali have been conducted in female Balb/cA nude mice bearing MDA-MB-436 tumor xenografts. The compound is administered via oral gavage at doses of 0.3, 1, or 3 mg/kg. Pharmacokinetic parameters, including absorption and tumor retention, are measured, and antitumor efficacy is evaluated by monitoring tumor growth inhibition.
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| ADME/Pharmacokinetics |
Fuzuopali is an orally active compound with good pharmacokinetic properties. It has a molecular weight of 472.40 and is soluble in DMSO (35 mg/mL). The compound is typically stored as a powder at -20°C for long-term stability. It has been approved in China for the treatment of recurrent ovarian cancer.
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| Toxicity/Toxicokinetics |
Specific toxicity data for fuzuopali is not extensively detailed in the search results. As a clinically approved PARP inhibitor for ovarian cancer, its safety profile has been established in clinical trials. Common adverse effects are consistent with other PARP inhibitors and may include hematological and gastrointestinal toxicities.
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| References |
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| Additional Infomation |
Fluzoparib is being investigated in the clinical trial NCT03863860 (a trial of fluzoparib versus placebo as maintenance therapy in patients with recurrent ovarian cancer). Fluzoparib is an orally administered inhibitor of poly(ADP-ribose) polymerase (PARP) types 1 and 2 with potential antitumor activity. After oral administration, fluzoparib inhibits the activity of PARP 1 and 2, thereby inhibiting the PARP-mediated base excision repair (BER) pathway for the repair of damaged DNA, enhancing the accumulation of DNA strand breaks, promoting genomic instability, and ultimately inducing apoptosis. The PARP protein family catalyzes post-translational ADP-ribosylation modification of nucleoproteins, which then transmit signals to recruit other proteins to repair damaged DNA. PARP inhibition may enhance the cytotoxicity of DNA-damaging drugs and may reverse chemotherapy and radiotherapy resistance in tumor cells.
Fuzuopali (Fluzoparib, SHR3162) is a potent, orally active PARP1 inhibitor with superior antitumor activity. It selectively targets HR-deficient cancer cells and has been approved in China for recurrent ovarian cancer. The compound demonstrates good pharmacokinetic properties and prolonged tumor retention in preclinical models. It is a research compound with clinical applications in oncology. |
| Molecular Formula |
C22H16F4N6O2
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|---|---|
| Molecular Weight |
472.395057678223
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| Exact Mass |
472.127
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| Elemental Analysis |
C, 55.94; H, 3.41; F, 16.09; N, 17.79; O, 6.77
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| CAS # |
1358715-18-0
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| PubChem CID |
56649297
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| Appearance |
White to off-white solid powder
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| Density |
1.6±0.1 g/cm3
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| Boiling Point |
748.5±70.0 °C at 760 mmHg
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| Flash Point |
406.5±35.7 °C
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| Vapour Pressure |
0.0±2.6 mmHg at 25°C
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| Index of Refraction |
1.690
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| LogP |
0.52
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
34
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| Complexity |
839
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1=CC=C(CC2C3C=CC=CC=3C(NN=2)=O)C=C1C(N1CC2=NC(C(F)(F)F)=NN2CC1)=O
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| InChi Key |
XJGXCBHXFWBOTN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H16F4N6O2/c23-16-6-5-12(10-17-13-3-1-2-4-14(13)19(33)29-28-17)9-15(16)20(34)31-7-8-32-18(11-31)27-21(30-32)22(24,25)26/h1-6,9H,7-8,10-11H2,(H,29,33)
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| Chemical Name |
4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one
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| Synonyms |
Fuzuloparib; SHR3162; SHR-3162; SHR 3162; Fluzoparib;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~33.33 mg/mL (~70.55 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1169 mL | 10.5843 mL | 21.1685 mL | |
| 5 mM | 0.4234 mL | 2.1169 mL | 4.2337 mL | |
| 10 mM | 0.2117 mL | 1.0584 mL | 2.1169 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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